Significance Chronic social and psychological stressors, prevalent in modern society, are important determinants of health and welfare. This research investigates in highly social primates, the consequences of social and environmental perturbations that challenge restoration of homeostasis and lead to lengthy periods of altered pituitary-adrenal regulation. Objectives This program of research is designed to evaluate the cognitive, immunological, and neurobiological consequences of stressors that produce chronic elevations and chronic reductions in pituitary-adrenal activity in rhesus monkeys. Results Much of the immunological and neurobiological research in chronic stress has relied on pharmacological manipulation of glucocorticoid levels. The assumption of this research, that it is stress-induced elevations in glucocorticoids that account for health risks associated with stress, has rarely been tested directly. Our research will utilize two models of chronic stress, which produce quite different forms of pituitary-adrenal dysregulation. The first model of chronic stress, repeated daily stress, has been widely used to understand how consequences of stressors can accumulate in time. We will use daily chair restraint, a physical and psychological stressor to which monkeys behaviorally adapt, but continue to elicit a substantial pituitary-adrenal response. Pilot data suggest that this type of repeated stress lead to chronic elevation of basal cortisol level. The second stressor-social instability--capitalizes on a broad-based understanding of the social interactions of monkeys and the evidence that alterations in the social situations of these monkeys provides naturalistic models of chronic stress. In contrast to the assumptions regarding the effects of physical stressors, social instability has been shown to produce long-term reductions in basal cortisol. Comparison of the two models of inducing chronic stress affords a unique opportunity to ask whether chronic stress subsumes multiple distinct syndromes, each associated with its own symptoms and risks. Future Directions We will begin detailed comparison of cognitive performance (using computer-assisted behavioral testing) and immunological competence in animals with chronically elevated or reduced glucocorticoids. Plans also include comparison of hippocampal structure and function in animals that have been subjected to chronic stress. KEY WORDS stress, cortisol, pituitary, adrenal FUNDING NIH Grant RR00169